The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We are measuring forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study is repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside are also being evaluated. Additional secondary studies are evaluating the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibit nitric oxide-mediated blood flow; markers of inflammation and oxidation; and gene expression by microarray and pilot studies of proteomics in sickle cell patients. As of 28 October 2003, we obtained IRB approval to begin these studies. We began enrollment in March 2004. We have enrolled 30 patients and 14 controls and have completed 25 studies in patients and 10 studies in controls. In preliminary analysis of the frist 15 patients, baseline vascular reactivity to arterial infusions of sodium nitroprusside (SNP), acetylcholine (ACh), and the inhibitor of endothelial NO synthesis, L-NG-monomethyl-L-arginine (L-NMMA) at increasing doses was assessed by forearm venous occlusion plethysmography. Patients took atorvastatin 10 mg daily for two weeks, then 20 mg daily for another two weeks, and forearm studies were repeated. All patients tolerated the drug without adverse effects. After atorvastatin treatment, serum total cholesterol levels decreased in all patients, (baseline 124+/-5 mg/dL, post-treatment 101+/-5 mg/dL (mean SEM), p=0.001, paired t-test). Serum creatine kinase increased slightly, but remained in the normal range. All patients had markedly impaired responses at baseline to SNP, Ach and L-NMMA compared to healthy control subjects, validating our screening methodology to identify subjects with NO resistance. After four weeks of oral atorvastatin therapy, responsiveness to both SNP (p=0.06) and ACH (p=0.05) improved in each group compared to baseline by ANOVA with repeated measures. Response to L-NMMA was not significantly affected. Because the results of the interim analysis did not meet the planned criterion for ending the study at that point (p<0.001 for increased L-NMMA response post-atorvastatin compared to pre-atorvastatin), enrollment until a total of 35 5 completed studies were performed. These data provide a non-invasive strategy for identifying patients with NO-resistance (endothelial dysfunction) by screening soluble VCAM-1 levels and tricuspid regurgitant jet velocities, and further suggest that high pulmonary artery systolic pressures in this population are associated with reduced NO bioavailability. Additionally, so far short-term use of the FDA approved medication atorvastatin, has produced no adverse effects in this population. In the oxypurinol portion of the study, trends are seen for increased vascular responsiveness to nitroprusside and acetylcholine (p<0.05), no change is yet discernable in L-NMMA responsiveness. We have seen no adverse effects with oxypurinol. Data collection is now complete for 25 patients and 10 controls and analysis is underway.